“What
a wonderful institution for the people who are
taken care of there—
for
the families of the people who are taken care of there and
for the
patients
themselves. But also what a wonderful institution for the
people
who
work there. It is a place that trains and respects and listens
to the
people
who are in there every day trying to literally save the world.”
– Cokie Roberts, congressional analyst for ABC News

In February 1999,
the front entrance moved to the south
side of Building 10 to allow for the
construction of the Mark O. Hatfield
Clinical Research Center.

In building a 14-story
research hospital with 500 research beds
surrounded by twice that number of scientific
laboratories, the idea was to create a self-contained
community of clinicians, scientists, patients,
and support staff, with the common goal of
conquering both chronic and acute disease.
In 1953, the idea of the government conducting
clinical research (research on patients)
was new and far from universally accepted.
Despite resistance to the idea, the vision
of three clear-sighted Public Health Service
officials— to strike a careful balance
between basic and clinical research— prevailed,
and the intramural program that centered
on the patient base in the Clinical Center
flourished. The NIH mandate was to produce
not new knowledge for the sake of new knowledge
but new knowledge that led to prevention,
treatments, and, where possible, cures. At
the end of World War II,“ the NIH was
an agency largely devoted to biology and
chemistry, and mice were the major experimental
subjects,” writes Alan Schechter. The
opening of the NIH Clinical Center “was
the culmination of the NIH’s transformation
from a small federal agency into the powerhouse
that has since propelled a large part of
all biomedical research in this country.”

Critical to the success
of the research enterprise was the proximity
of research labs to patients. Before, research
tended to be divided into two cultures: clinicians
doing case studies or drug studies and basic
scientists working in the laboratory. The
Clinical Center’s innovative physical—and
philosophical—structure permitted a
single scientist to work in both the lab
and the clinic. More importantly, it encouraged
informal interactions in the corridors between
clinicians and basic scientists. That as
much as anything permitted physician-scientists
first to get an education and then to stay
scientifically alive. The physical set-up
of the Clinical Center encouraged a cross-fertilization
of ideas, enhanced by the presence in one
building of trained, intelligent, and devoted
caregivers; a critical mass of intellectually
curious scientific and medical experts; and
the world’s best supply of patients
with rare and research-worthy medical conditions.
Finding solutions to those patients’ medical
problems through cutting-edge research would
be the Center’s sole mission, guiding
all its activities. The physical presence
of the patients in Building 10 would remind
them of the urgency of that mission.

The excitement of the new
venture drew bright young investigators from
all over the world, who came to learn, make
their mark, and (usually) return to their
home institutions. Given full support, they
made discoveries at an amazingly rapid rate.
The Center got off to a strong start partly
because of a brilliant recruiting device:
during the Korean and Vietnam wars, the doctor
draft brought many bright young physicians
to Bethesda for what they thought was a two-year
stint, an alternative to military service.
Many of the great names in medical science—physicians
like Tom Waldmann, Vince DeVita, and Tony
Fauci —got hooked on research and stayed.

The spectacular launching
of clinical research in 1953 also spawned
a generation of research scientists in the
1950s and 1960s who left and established
new centers of scientific creativity throughout
the United States. In what for decades was
known (in classic government jargon) as Building
10, the Clinical Center became a center for
studying and training in clinical research
as much as it was a place to do clinical
research. “For the past 50 years the
Clinical Center has provided a place where
the most creative, brightest doctors in the
country could come, train, and become leaders,” observes
Elias Zerhouni, director of the National
Institutes of Health. “When I go around
the country, I’m amazed at the number
of people who have trained here, who had
their experience as clinician scientists
at the Clinical Center here at NIH. ”

Roy Hertz admitted the
Clinical Center’s first patient—Charles
Meredith, a Maryland farmer with prostate
cancer—on July 6, 1953. Since then,
NIH investigators have seen more than a quarter
million patients. In the early years, there
were far fewer institutes than there are
today. The bed activation schedule for 1953-54
shows the Cancer institute with the most
beds, at 35; Mental Health, Heart, Arthritis,
and Microbiology had 25 beds each, and Neurology,
15. Today 20 institutes and centers see patients.
With 6,000 scientists on campus, the Bethesda
campus contains the most powerful concentration
of biomedical scientists in the world.

It’s the institutes
that do the science, conduct most of the
research that goes on in the Clinical Center,
and produce so many Lasker Award and Nobel
Prize winners. Much basic science work goes
on before someone comes up with an intervention
such as a vaccine, treatment, or approach
to diagnosis for a medical condition. The
Clinical Center is the final common pathway
for translating scientists’ work in
labs and with animal models into natural
history studies, medical interventions, or
clinical trials with human patients. In the
Clinical Center, scientists and clinicians
working together with a broad-based team
of other experts establish proof of principle.
In recent years the number of protocols involving
multiple institutes has increased dramatically.
The nature of science in the twenty- first
century is inherently collaborative, and
collaboration is the Clinical Center’s
strong suit.

Clinical trials of new
drugs account for roughly half the protocols
in the Clinical Center. Most of the clinical
trials conducted here have been phase 1 or
2 trials, for safety and efficacy—the
first time these agents have been tested
in humans. After these early studies, the
drugs move into phase 3 trials, which are
usually conducted off-campus in large populations
by extramural researchers. Back at the Clinical
Center, intramural researchers then turn
their attention to other challenges requiring
innovative or untested research that couldn ’t
easily be done elsewhere.

The other half of the protocols
involving Building 10 are natural histories
of diseases—often rare diseases—to
elucidate their pathogenesis and to develop
new medical interventions or approaches to
diagnosis, prevention, and treatment. The
natural history studies are typically long
term and usually involve patients from all
over the nation and sometimes the world.
Many of them probably would not have been
done if they had not been done in the Clinical
Center.

Building
10, which opened as the NIH Clinical
Center in 1953, was the tenth
structure built on the Bethesda
campus. It was unusual even in
its naming: It was called a “clinical
center,” not a hospital.
Along one corridor and in the
wings of the huge red brick building
were laboratories; along the
south corridor were patient rooms
and a hospital. The hospital
occupied less than half the space
of the Clinical Center. The idea
was to bring both basic and clinical
science to the patient’s
bedside. That concept has been
followed in most of the construction
that’s taken place within
and around the Clinical Center.

“We do three things
here: medical research,
patient care, and construction,” visitors
are often told. Designed
for flexibility (to accommodate
changing protocols),
the Clinical Center began
and remains in a constant
state of growth and renovation.
Renamed the Warren G.
Magnuson Clinical Center
in 1979, in honor of
a loyal senatorial supporter,
the Clinical Center expanded
significantly with the
addition in 1982 of the
Ambulatory Care Research
Facility (ACRF) to accommodate
the growing demand for
outpatient care. As the
length of the hospital
stay decreased and outpatient
medicine grew (recently
with day hospital stations),
the need for patient
beds in the hospital
declined to the current
steady-state level of
about 240 beds.

The newest addition
to Building 10 is the
Mark O. Hatfield Clinical
Research Center (the
CRC), also named to honor
a senator, opening in
2004. The CRC will allow
rapid changes in hospital
settings—for example,
to accommodate patients
with special needs or
disease conditions that
require isolation. The
Magnuson and Hatfield
Centers combined will
be the NIH Clinical Center—all
still part of Building
10. Aiding in the renewal
promised by the Hatfield
Center are two buildings
that support patients
and families in the Clinical
Center, the Children’s
Inn and the new Safra
Family Lodge (also opening
in 2004).

A short list of research
advances that have taken place in the Clinical
Center would include the following:

First cure of a solid tumor with chemotherapy

First chemotherapeutic cures for childhood
leukemia and Hodgkin’s disease

First use of immunotherapy to treat cancer

Evidence of a genetic component in schizophrenia

First successful replacement of a mitral
valve

Use of nitroglycerin for acute myocardial
infarction

First controlled trials of lithium’s
effect on depression

Analysis of the disorders of lipid metabolism
and the pathogenesis of arteriosclerosis

And that just skims the
surface of clinical research achievements
in Building 10. The mini-history in this
program is a sampler of stories of research
and patient care being gathered for a brief
history of the Clinical Center, currently
in preparation.

Pioneering
in chemotherapy

Histories of the NIH intramural
program often refer to the 1950s and the
1960s as the “golden years,” and
so they must have seemed when so many bright
investigators were striking out in bold new
directions and laying the foundation for
biomedical research for decades to come.
But the path to remarkable medical achievements
was not always easy. Major advances in cancer
research came early in Building 10, for example,
but were not wholeheartedly welcomed at the
time.

A young Chinese postdoctoral
medical fellow, Min Chiu Li, brought from
Sloan-Kettering some women with gestational
choriocarcinoma, a rapidly fatal and rare
cancer of fetal tissue of the placenta. Ann
Plunkett, one of the first nurses on the
cancer service, recalls, “They would
come in, these young women, and die within
a matter of weeks to months.” Li proposed
to Roy Hertz administering large doses of
a new folic acid antagonist, known now as
methotrexate, and was allowed to decide for
himself whether to proceed. At first the
drug made the patients ill; then one patient
responded, and a second, and a third. “It
made you a real believer in medical research,
to see these young women begin to live,” says
Plunkett. In 1957, with single-agent chemotherapy,
they had achieved not just remission, but
a cure—the first successful chemotherapeutic
cure for malignancy in a human solid tumor.
Because it was an unusual tumor, with an
immunological component (the placenta being
considered tissue the mother’s body
could reject), that first success was attributed
to “spontaneous remission.” Nobody
would accept it as proof that chemotherapy
could cure cancer, and Li was asked to leave
NIH.

In the 1960s, against strong
external resistance from a cancer community
that felt the science wasn’t ready
for it, the National Cancer Institute’s
Emil (“Tom”) Frei and Emil (“Jay”)
Freireich introduced intensive combination
chemotherapy for the treatment of acute lymphocytic
leukemia of childhood. They were aware of
preclinical studies of combination chemotherapy
by Howard Skipper and Abe Goldin. They had
seen Lloyd Law, one of the first NIH “mouse
doctors,” have some success administering
combination chemo to leukemic mice. At a
time when a diagnosis of leukemia was a death
sentence, the two Emils decided to try combination
chemotherapy in leukemic children. They administered
four different drugs, with non-overlapping
toxicity (so you could use them at full dose),
which attacked cells at different phases
of the cycle. It had been shown that combinations
of drugs had a synergistic, not just an additive,
effect, so there was some reason to think
combination chemotherapy would work, and
they had strong support from their boss,
NCI’s Gordon Zubrod, who proposed dividing
clinical trials with new cancer drugs into
three phases.

In those days, mainstream
cancer researchers considered surgery and
radiotherapy to be the only appropriate treatments
and strongly denounced Frei and Freireich’s
approach as “toxin of the month.” But
Frei and Freireich produced the first cure
by chemotherapy of a childhood cancer and
helped establish the intramural cancer institute
as willing to take high risks for high rewards—based
on evidence of a good chance an experiment
will work. At first, only a small percentage
of the young leukemia patients treated were
cured, but the research has continued, and
today acute lymphocytic leukemia is curable
in 80 percent of children. Now NCI is testing
the long-term effects of radiation therapy
given long ago for children with leukemia
that had reached the brain (most drugs do
not cross the blood-brain barrier).

A young clinical associate
named Vincent DeVita would take the lead
in similar work on Hodgkin’s disease,
the first adult cancer of a common organ
system to be cured by chemotherapy. And in
the multidrug therapy trials for Hodgkin’s,
huge proportions of the patients treated
were cured.

Li, Frei, Freireich, and
DeVita were asking the question, “Could
you ever cure advanced cancer with chemotherapy?” at
a time when cancer was believed to be an
incurable disease, and chemotherapy was regarded
by many as the cruel use of toxins in patients
already facing certain death. “Tom
Frei created the environment where you could
ask the question,” recalls Vince DeVita,
now at the Yale Cancer Center. “No
other institution in the world would even
dare to ask that kind of a radical question.
Between the two diseases we proved the point,
that cancer could be cured with chemotherapy— something
that’s been subsequently proven many
times over. You had to have a place like
the Clinical Center, and you had to have
people who were willing to let the unaddressable
questions be addressed.” The Clinical
Center became the center for “proof
of principle.”

“I don’t think
it could have been done elsewhere,” says
Tom Frei, now at the Dana Farber Cancer Institute. “We
were definitely swimming upstream. And you
had people who were totally devoted to that
program. In practice we see patients with
various diseases, for the most part, and
that’s essential for good practice,
but it doesn’t allow for the kind of
focus that we were able to achieve in one
disease for a long period of time. Taking
care of patients today is a major effort—all
the reading and studying and talking to basic
scientists, working in laboratories, developing
protocols, working with lab technicians—that’s
a big effort. We were fortunate in that we
were allowed to focus just on the one disease
and the things we needed for that one disease.”

More conservative academic
cancer researchers considered Frei and Freireich
to be “just maniacs,” says DeVita,
who is writing a book about the war on cancer. “They
were really taking a terrible beating in
those days. Cancer was a fatal disease, and
the idea that chemotherapy could cure it
was only in the thoughts of people who were
somewhat deranged. I’m only slightly
exaggerating. Gordon Zubrod fought the battles
at the higher levels, to allow people like
Frei and Freireich and myself to do things
that otherwise couldn’t possibly be
done. He provided a protective umbrella over
us, and it paid off. But in those days I
think we couldn’t have done it anywhere
but the Clinical Center.”

“Medicine doesn’t
just move smoothly forward,” says DeVita. “Strong
feelings influence what goes on and what
people can do, and in the environment of
the Clinical Center, although those strong
feelings existed, you still had the freedom
to move, whereas strong feelings at a university
would stop you cold because any tenured professor
can object to something. You needed to do
it in a place like the Clinical Center, and
then it opened the door for the same things
to be done at Yale, and Harvard, and so on.”

Using high-dose regimens
to destroy tumors successfully treated the
underlying diseases, leukemia and Hodgkin’s,
but often destroyed bone marrow. With too
few platelets, the patients could bleed to
death; with too few white blood cells, they
would develop opportunistic infections. NCI
and the Clinical Center staff together developed
techniques to support intensive combination
chemo, including transfusions of white cells
and blood platelets. Freireich and his colleagues
pushed for development of machines to remove
platelets from normal volunteers’ blood
for infusion into cancer patients undergoing
chemotherapy. NCI investigators, in collaboration
with George Judson, an IBM engineer, developed
what became the IBM 2990 blood cell separator,
still considered the most effective means
for collecting adequate numbers of leukocytes
from normal donors. Freireich was also involved
in infusing white blood cells into the patients.
To provide a germ-free environment, a laminar
air flow room was installed on 13 East, which
took its first cancer patient in 1969 and
was later used to treat patients with severe
combined immunodeficiency (SCID).

M.C. Li finally did get
recognition for his early work in chemotherapy.
In 1972, most of the Lasker Awards presented
for research on cancer treatment went to
researchers in the Clinical Center: Paul
P. Carbone, Vincent T. DeVita, Jr., Emil
Frei III, Emil J. Freireich, Roy Hertz, James
F. Holland, Min Chiu Li, Eugene J. Van Scott,
and John L. Ziegler, with a special award
to C. Gordon Zubrod. More importantly, these
investigators provided invaluable training
to many others. Vince DeVita alone trained
93 people, a third of whom have gone on to
head cancer centers around the country.

Immunology:
another frontier

Paralleling the intramural
cancer program’s leadership in chemotherapies
for cancer has been a track in biological
approaches, based on deepened understanding
of how the body’s immune system works.
Tom Waldmann and Bill Paul were pioneers
in figuring out how interleukins (cell signaling
molecules) were involved in immunological
responses. The NIH became a center for researching
interleukins and establishing new approaches
to the treatment of both cancer and immunological
diseases. Research in the 1960s defined the
survival of all the classes of immunoglobulin
(antibody) molecules: which parts of the
molecule controlled survival and how long
they survived. Learning about the very long
survival of an IgG molecule provided the
scientific basis for the use as therapeutic
agents of monoclonal antibodies—antibody-like
substances developed from a single line of
B cells, targeted to a specific disease.

NIH became phenomenally
strong in immunology. Some researchers began
studying genetic immunodeficiency diseases,
not because they’re big public health
problems but because they involve a single
genetic defect, so they can provide a lot
of information about what is essential for
immune system responses, such as T cells,
B cells, and antibodies. For decades, researchers
in NIAID have been developing immunosuppressive
therapy for nonmalignant diseases such as
lupus. Shelly Wolff and Tony Fauci in the
National Institute of Allergy and Infectious
Diseases (NIAID) had produced the first “cure” of
a formerly lethal non-neoplastic disease,
Wegener’s granulomatosis, by using
low doses of cytotoxic agents. John Gallin
and colleagues applied immunotherapy to boost
host defenses to prevent infections in patients
with chronic granulomatous disease of childhood,
using interferon gamma, and Harry Malech
has made important advances toward gene therapy
for the same disease.

As director of NIAID, Richard
Krause predicted in his book The Restless
Tide, completed in 1980, that we had not
seen the last of infectious diseases (at
a time when many scientists felt it was time
to move on to more pressing health problems).
Krause had built NIAID into an institute
with strength in basic and clinical immunology.
Many investigators studying human immune
deficiencies had significantly advanced understanding
of how the immune system works and how it
goes awry. That knowledge would be useful
when HIV and AIDS came along. So would work
done in the Clinical Center’s Blood
Bank.

Cleaning
up the blood supply

The Blood Bank had published
its first research paper delineating the
problem of post-transfusion hepatitis in
1957. Years later, a clinical associate named
Harvey Alter would play a crucial part in
solving that problem, though doing so would
take decades. His story illustrates how easily
collaborations form in the Clinical Center
and how unexpected and long the paths to
success in research may be.

In the 1960s, Alter was
trying to figure out why patients developed
high fevers in reaction to transfused blood. “We
knew that some people reacted to white cells
and to red cells but a lot of people seemed
to be having febrile transfusion reactions
that weren’t explained. My theory was
that people might be reacting to plasma proteins
that were different from their own.” Alter
had set up a method for testing the serum
of repeatedly transfused patients against
the serum of donors, which produced a precipitant
line in agar, reflecting the presence of
antibodies. One day a colleague told Alter
that he’d just heard a lecture by Baruch
Blumberg, a geneticist with Arthritis and
Metabolic Diseases, and that Blumberg was
studying analogous precipitant lines.

“The beauty of NIH
is that I went to talk to him the very next
day, and by that evening we had established
a collaboration,” says Alter. Their
work together led to the discovery in 1964
of the Australian antigen, which Blumberg
later showed to be the surface coating of
the hepatitis B virus, which led to the isolation
of this medically important virus.

In the ’50s and ’60s,
the technology for open-heart bypasses was
in its infancy, and several units of blood
were required just to “prime” the
oxygenator used in surgery, so cardiac patients
typically received 14 to 17 units of blood.
There was much less concern then about the
risks of blood transfusion, and blood was
used liberally. The Blood Bank was concerned
that this might lead to a high rate of transfusion-transmitted
infection, especially hepatitis. Alter took
specimens from each of the donors for open-heart
surgery. He also took samples from the surgery
patients, before and after surgery and then
continually for their lifetimes—the
frequency of the sampling depending on whether
or not he found any evidence of transfusion-transmitted
hepatitis. Unfortunately, about a third of
those patients had received tainted blood,
which eventually inflamed their livers, producing
hepatitis.

Alter froze and stored
those donor and patient specimens, which
required an enormous serum repository. Initially
he put the samples in freezers in the Clinical
Center, then in a rented meat locker in Tyson’s
Corner, Virginia, and eventually in a professional
facility from which specimens could easily
be retrieved when needed. “This all
evolved at a time when such a repository
was quite expensive and simply wasn’t
done, and this turned out to be a gold mine,” says
Harvey Klein, who became department director
in 1984, the year the Blood Bank was renamed
Transfusion Medicine.

Studies done in 1970 had
shown that patients who got one unit of paid-donor
blood had about a 50 percent chance of getting
hepatitis, whereas if they got only volunteer
blood, that chance dropped to 7 percent,
a dramatic difference. The Blood Bank had
been buying about half its blood from outside
sources— classic commercial blood establishments
in Baltimore and Memphis at which donors
often sold their blood to buy alcohol and
perhaps other drugs as well. So in 1970 the
Blood Bank switched to an all-volunteer system,
at the same time adding a test for hepatitis
B surface antigen. Prospective studies done
later showed that those two measures alone
reduced the hepatitis rate from 30 percent
before 1970 to about 11 percent after. “In
truth,” says Alter, “nothing
we’ve ever done since that time has
had that dramatic an impact because there
were so many cases to prevent.” When
they added more sensitive tests, hepatitis
B virtually disappeared as a problem in the
Blood Bank. These policies were soon made
national standards.

In collaboration with Bob
Purcell and Stephen Feinstone (NIAID), Alter
determined that whatever was triggering the
rest of the transfusion- associated hepatitis
was neither hepatitis A nor hepatitis B.
From 1975 to 1989 they called the unknown
agent(s) “non-A, non-B hepatitis” (NANBH),
showed that it produced antibodies in a chimpanzee,
and searched for a simple serologic test
to distinguish those who carried the infection
from those who didn’t. So many laboratories
claimed to have produced tests for NANBH
that from his warehouse of frozen samples
Alter developed a coded, well-pedigreed panel
of specimens, some of which were known to
be non-A, non-B cases, and some of which
were controls. It was a tricky panel, and
only Alter held the code to it. Roughly 40
labs asked to have their tests applied to
the panel, and none had produced a successful
test. In 1989 a commercial firm named Chiron,
which had secretly been working to clone
the non-A, non-B agent since 1983, told Alter
it had developed a test it wanted him to
run against his panel. The test worked; it
broke the panel.

The beauty of having a
repository of well-followed, highly pedigreed
patient specimens, says Alter, was that they
could truly show they had found the marker
for what they now named “hepatitis
C.” They published a paper in the New
England Journal of Medicine (“the fastest
paper I ever wrote”), and by 1990 had
a first-generation test in place in all of
the blood banks in the country. “This
kind of long-term, nondirected research could
really only have been done here at the Clinical
Center,” says Alter. “If I had
gone to a granting authority in 1970 and
said, ‘I don’t know what hepatitis
agents are, but I think there are some out
there and I want to find them, and I want
to follow patients long term because the
natural history of hepatitis C or non-A,
non-B, is 20, 30, 40 years—it’s
a very slowly evolving infection—so
I’d like to be funded for about 30
years and really study this . . .’ I
couldn’t do it! But here at NIH each
year I would get some money to do something
and just kept going.

“It’s an amazing
place in which to engage patients and particularly
to strike up collaborations,” says
Alter. “It’s so easy to work
with other people, to get expertise you don’t
have, to get patients who are interested
and grateful and participate in studies with
great enthusiasm. There’s no money
involved, and you don’t have to discharge
a patient at a given time. Both you and the
patient know that you’re here to find
out what’s wrong, to study many patients,
and to publish the results. So both patients
and physicians come in with a totally different
perspective than in a regular hospital. The
ability to do studies depends on the patients’ confidence
in the people taking care of them, and the
nurses play a dramatic role in this. Increasingly
nurses really run studies, so it’s
way more than just peripheral involvement—they’re
very heavily involved. The whole place is
geared to work that way and also to work
between institutes, between departments—whatever
it takes to make information evolve and to
help the patient at the same time.”

In 1976, Baruch S. Blumberg
received a Nobel Prize for his work on the
Australian antigen and hepatitis B. In 2000,
Harvey Alter and Chiron’s Michael Houghton
shared a Lasker Award for their work. Alter,
elected to the National Academy of Sciences,
has been widely recognized for reducing the
risk of blood transfusionassociated hepatitis
from 30 percent in 1970 to virtually zero
in the year 2000. According to FDA, the risk
of contracting hepatitis B from a pint of
blood is now 1 in 200,000; the risk of contracting
hepatitis C, about 1 in 2 million.

When, in the early 1980s,
a new disease came along, an acquired disease
of severe immunodeficiency, there was a suspicion
it might be transmitted by blood, but no
one was really sure. The work done in the
Blood Bank—and that repository of frozen
blood specimens—became important both
for AIDS generally and for the safety of
the nation’s blood supply. And so would
work done elsewhere in NIH’s intramural
program.

Addressing
the AIDS crisis

On June 16, 1981, Thomas
Waldmann admitted a 35-year-old white male
patient to the Clinical Center under an NCI
protocol. Waldmann and his colleagues didn’t
know what to make of his condition: multiple
infections and a dangerously low white blood
cell count. Six months later, during a snowstorm
that shut down the government, a second patient
with similar symptoms was admitted and was
seen by Tony Fauci, a senior investigator
with NIAID. There would be many more before
scientists knew exactly what they were dealing
with.

In 1981, nobody had the
faintest idea how this strange new immune
disorder worked, except that it appeared
to be transmitted by blood and through sex.
Early reports convinced Fauci that the emerging
disease could become a disaster, spreading
well beyond the community of gay men and
drug abusers where it had first appeared.
He quickly redirected his branch’s
work almost totally toward studying the disease.
Most of the investigators who joined him
put aside most of the work they had been
doing on other diseases to help with what
could clearly become a medical crisis. The
institutes could mobilize an intramural army
of researchers to attack the problem faster
than other institutions because the infrastructure
was in place and funding could be rapidly
shifted (the intramural staff did not have
to write grant applications).

In June 1982, a Clinical
Center protocol was approved to study the
etiology of immunoregulatory defects in the
new disease as a collaborative effort among
Clinical Center departments, NIAID, NCI,
the National Institute of Neurological Diseases
and Communicative Disorders and Stroke (NINCDS—now
NINDS), the National Institute of Dental
Research (NIDR), the National Eye Institute
(NEI), and the Food and Drug Administration
(FDA). An NIH working group was set up to
study the new disease, with representatives
from each institute and liaisons from CDC
and FDA.

Fauci converted his lab
from one that explored fundamental questions
of immunology to one that focused on understanding
this new disease. Joe Parillo, head of the
Clinical Center’s new critical care
department, agreed to take patients if he
could hire a specialist. Henry Masur—son
of the Clinical Center’s first director,
Jack Masur—had been working in New
York when he observed a strange increase
all around the country in Pneumocystis carinii,
a rare cause of bacterial pneumonia usually
seen only in patients with severe immune
disorders. Masur agreed to join the Clinical
Center staff because he sensed it would be
easier to tackle a complex emerging disease
in a place with experts on almost everything,
a place where physician-scientists were free
to follow their own interests.

The Clinical Center began
admitting more patients with this complex
array of symptoms. The hospital focused on
only a few patients at first, providing intensive
care but always in a setting of clinical
investigation. It “was like living
in an intensive care unit all day long,” says
Fauci. Most of those first patients eventually
died despite the best efforts of NIH’s
dedicated and initially anxious doctors and
nurses.

Scientists describe as “elegant” the
work Fauci, H. Ciff Lane, and others did
in figuring out the pathogenesis of AIDS.
In their laboratories, they proved that during
long periods when the infectious agent was
lurking, silent and invisible, it was nevertheless
wreaking havoc in the molecular architecture
of the human lymph nodes, destroying the
immune system. They worked on strategies
to restore immune defenses. Lane observed
that patients with AIDS lacked helper T cells
but had markedly hyperreactive B cells—the
cells that make antibodies. Lane concentrated
on understanding the immune system abnormalities
in AIDS patients and looked for ways to stop
the disease. He and his colleagues tried
bone marrow and white blood cell transfers
from healthy twins to their identical siblings
with AIDS. They tried alpha interferon, interleukin-2,
and other agents.

As a complex syndrome of
opportunistic infections and other diseases
brought about by a failing immune system,
AIDS drew intramural NIH researchers from
many disciplines. Soon a “grassroots” team
of scientists were working together, routinely
sharing observations. That AIDS was so complex
made it both difficult and fascinating to
study. Researchers in NIDR, for example,
showed that the AIDS virus could infect not
only T4 lymphocytes but also macrophages.

David Henderson, the hospital’s
first official epidemiologist—and now
Clinical Center deputy director for clinical
care—led the team charged with reducing
the risk of health professionals becoming
infected with the disease, even before the
virus and its mode of transmission were identified.
For a while it was a full-time job keeping
hospital staff up to speed on what the known
and unknown risks were and how to reduce
them. Aided by nurses such as Barbara Fabian
Baird and Christine Grady—and many
others on the front lines of the AIDS crisis—Henderson
developed guidelines for protecting healthcare
workers from infection.

In some ways previous decades
of research at the Clinical Center—before
AIDS came into public awareness—had
prepared its physician-scientists to deal
with the problem. Had it come along thirty
years earlier, they would not have known
enough to be able to look for the retrovirus
that caused AIDS or to be able to grow continuous
cell lines so they could study it. In 1979,
Robert C. Gallo Jr. in NCI had discovered
the first human retrovirus, human T-cell
lymphotrophic virus, or HTLV-I—at a
time when most scientists believed retroviruses
occurred only in cats, mice, and other animals.
To be able to do this, he had first developed
methods (based on the discovery by others
in his lab of the interleukin hormone IL-2)
for growing human T cells in culture. Because
HTLV-I caused an obscure cancer of the immune
system, little attention had been paid to
the discovery.

In 1982, Gallo had proposed,
and was working under the assumption, that
the new disease was caused by a retrovirus.
By 1984, research groups led by Gallo and
investigators in Paris and California had
all simultaneously identified a retrovirus
as the cause of AIDS (calling it HTLV-III,
LAV, and ARV). Renamed human immunodeficiency
virus, or HIV, the virus provided a target
for research. Gallo’s laboratory developed
a diagnostic antibody test, which allowed
researchers to get a sense of the scope of
the epidemic and gave healthcare workers
the ability to screen blood donors and protect
the blood supply. Gallo’s location
on NIH’s main campus and his constant
interactions with the Clinical Center, from
which his lab received tissue samples and
peripheral blood specimens, unquestionably
accelerated his seminal discoveries.

“This
hospital is a jewel in the medical
universe. For someone like myself
who wants to do serious science and
seriously apply it—in my case,
finding new treatments for patients
with cancer—there’s no
place in the world like the Clinical
Center of the National Institutes
of Health.

“We have spectacular
research resources. We have
250 state-ofthe- art hospital
beds married to world-class
research facilities and world-class
scientists—over 2,000
PhDs who are doing basic
scientific research, eager
to collaborate with clinicians.
Half of all the clinical
research beds in the United
States are in this building,
paid for by the U.S. government
for the sole purpose of developing
improved management for patients.

“This gives us an
opportunity to do things
that would be very, very
difficult to do elsewhere.
We can bring patients into
the hospital and perform
studies in a scholarly way
that would be impossible
if patients were paying for
their care. The beds are
available to do research
and to look at experimental
means for managing and treating
patients in our care. We
don’t have to worry
about the $2,000 a day that
patients are paying in most
hospitals. We have no emergency
ward or trauma center. No
local population depends
on us for care. We can control
patient flow so that the
only patients we bring into
this hospital are patients
who can help us answer questions.
We might accept only one
out of every ten patients
referred to us. Our community
is the world of patients
who have intractable medical
problems. The patients are
the explorers—in a
sense, the adventurers—experiencing
new treatments for their
own benefit and for the benefit
of patients who follow.

“We have our own
research laboratories literally
a few steps away from our
patient wards, and often
we literally carry the materials
we develop from the laboratory
to the patient wards for
treatment. This intermingling
of scientists with clinicians
and clinician-scientists
creates an environment that
is unsurpassed for enabling
innovative, groundbreaking
research.”

– Steven A. Rosenberg, NCI,
pioneer in cancer immunotherapy

When Fauci took over as NIAID’s director
in 1984, in addition to overseeing laboratory
and clinical research, he helped convince
Congress to dramatically increase funds for
AIDS research. NIAID’s scientific director,
John Gallin, who helped create the first
AIDS clinic at the Clinical Center, coordinated
NIAID’s on-campus fight against AIDS
when (in 1986) Congress gave the scientists
the funds they sought. An important spinoff
of the AIDS epidemic was stronger patient
advocacy and activism. As unofficial spokesperson
for the government during the crisis, Fauci
drew the public ire of playwright Larry Kramer,
co-founder of Act-Up and a proponent of theater
tactics. By engaging in a productive dialogue
with Kramer and other protesters, Fauci helped
introduce more active patient representation
in Clinical Center decision-making. Gallin,
when he later became Clinical Center director,
strengthened that emphasis.

When the epidemic started, NCI was the only
institute involved in drug development in
areas the private sector ignored. Most of
the institutes looked down on drug development,
and most scientists insisted that viruses
were unaffected by drugs. But Sam Broder,
a physician-researcher at NCI, began testing
several agents for their effectiveness in
blocking replication of the AIDS virus. Working
with him were Hiroaki (“Mitch”)
Mitsuya (who “could grow anything in
tissue culture”), Robert Yarchoan,
and others in the intramural program. There
was a window of two to three years, says
Broder, between 1984 and 1987, where “everything
sort of clicked in and the bureaucracies
were not there to do what bureaucracies usually
do....among the reasons why I think bureaucracies
stayed away is that there was a strong presumption
that the project would fail quickly or self-destruct....
I was also willing to accept that it is better
to make some progress quickly than hold back
and wait for a cure before acting or before
trying to implement a new therapy.” He
had the full support of NCI’s director,
Vince DeVita, who, says Broder, “had
a belief that you can do things without having
to wait for perfect knowledge, and he was
not afraid to act.”

One of the agents Broder’s team tested
was a chemical that had been rejected as
an anticancer agent: Broder and his colleagues
pulled AZT off the shelf and tested it against
AIDS. Yarchoan recalls being particularly
impressed by AZT’s dramatic effect
on one patient, a nurse from New York, “who
had gotten AIDS through a blood transfusion
and had a horrible fungal infection of her
fingernail. Her nail was quite ratty. When
we gave her AZT, the infection cleared up,
and you could see where the normal nail was
starting to grow.” Children whose mothers
had infected them with HIV at the time of
delivery looked flaccid and nearly dead.
Infused with the drug over several days,
they were soon sitting up and behaving like
normal children. That caught the attention
of the pharmaceutical firm known then as
Burroughs Wellcome, which became interested
in developing the drug. In March 1987, the
FDA approved AZT as the first antiretroviral
drug to be used as a treatment for AIDS.
Broder’s group led studies on AZT’s
antiretroviral cousins, ddI and ddC.

In many ways, the Clinical Center’s
handling of the AIDS crisis was no different
from its handling of earlier disease problems,
including the first attempts to cure cancer
with chemotherapy: a few interested investigators
simply dug in and attacked the problem from
as many angles as necessary. “The great
thing about the Clinical Center,” says
Henderson, “is that it can turn on
a dime. You could say, ‘This is a national
public health problem. Deal with it,’ and
we could figure out how to restructure our
resources and get started the next day.” Because
intramural researchers are free to follow
their interests—to go where the science
leads them—it was relatively easy to
redirect resources to the new crisis. Once
more it had been shown that, given enough
funding, scientists and clinicians could
address even so large a problem as AIDS.
And the work continues—in particular,
efforts to develop a vaccine.

“The very compactness of the Bethesda
campus and the willingness of its immunologists
to work together, to have seminars constantly,
and wander in and out of each others’ labs
gave them a leg up,” observed Edward
Shorter, commenting on NIH’s intramural
program in his book The Health Century (1987). “At
centers where in-house competition was fiercer,
such as Harvard, people were more secretive.
At the state universities, the sheer number
of researchers, however excellent they were
individually, did not achieve that critical
mass. But NIH, like Baby Bear’s porridge,
was just right. An AIDS researcher at NIH
explained...‘if you take an institutional
climate of informality and unlimited support
and bring the right people on board, something
is going to happen.’”

Studying genetic
diseases

After the development in the 1970s of recombinant
DNA techniques for cloning genes and of techniques
for identifying and sequencing DNA fragments,
intramural protocols aimed increasingly at
elucidating the pathophysiology and treatment
of genetic diseases. One of the first such
studies was closely linked to earlier studies
in the National Heart, Lung, and Blood Institute
of the disorders of lipid metabolism and
the pathogenesis of arteriosclerosis.

Among the most beloved of NIH researchers
(and for a period NIH director), Donald Fredrickson
brought attention and understanding to a
rare genetic disorder that he named Tangier’s
disease, for an island where it occurred
with some frequency. He, Robert Levy, and
Robert S. Lees developed a clinically useful
biochemical and genetic classification of
blood lipids and lipid abnormalities. Their
classification of hyperlipidemias did not
stand up to the test of time, but their important
work led to our current classification of
risk factors for coronary artery disease
and to popular understanding of things like
good cholesterol and bad cholesterol. For
this work, the Clinical Center was invaluable
not only because it is one of the only places
in the world that conducts long-term studies
of rare diseases, but also because it brings
patients with these diseases to the Clinical
Center from all over the country and sometimes
all over the world.

Experiences with such patients at the Clinical
Center often affected young physician-scientists
long after they completed their training
there, indirectly generating important biochemical
research later and elsewhere. As clinical
associates in 1968-70, for example, Michael
S. Brown (working in Earl Stadtman’s
laboratory in Arthritis and Digestive Diseases)
and Joseph L. Goldstein (working in Marshall
Nirenberg’s lab in NHLBI) were intrigued
by two young patients of Donald Fredrickson’s.

As clinical associates, the two men spent
one year taking care of NIH patients and
a second year doing research. One of their
patients was a long-time Clinical Center
patient, Al Cohen, who because of an inherited
condition (abetalipoproteinemia) had no LDL
in his blood (LDL being a low density lipoprotein,
the major cholesterol-carrying particle in
human blood). They also saw a brother-sister
pair with excessive levels of LDL (their
total blood cholesterol levels of about 1000
milligrams per hundred milliliters being
nearly ten times above normal for children
aged 6 and 8). These siblings’ condition,
known as homozygous familial hypercholesterolemia,
had produced severe atherosclerosis, so they
were having heart attacks in childhood. “Dr.
Goldstein and I became fascinated with these
patients,” says Michael Brown, “and
we decided that we would figure out how genes
control the LDL level in blood, and why some
people have no LDL and others have enormous
levels. These patients are very rare—they
are only one in a million—so the chance
that we would ever see a patient like that
again was extremely small. But we remembered
those children and we set up a research program
to try to figure out how the body normally
controls the level of cholesterol in the
blood and why the level should have been
so high in those children. If we hadn’t
seen those children at NIH, we would have
never known about this illness, and we would
have never worked on the problem.”

In 1972, they began to collaborate on studies
of familial hypercholesterolemia at the University
of Texas Southwestern Medical School, where
they made use of Al Cohen’s plasma
and of cells from patients with familial
hypercholesterolemia. “We could only
have seen these patients at NIH, because
both genetic diseases are extremely rare,
and only NIH would have been able to bring
these patients together,” says Brown.
In 1985 they won the Lasker Award and the
Nobel Prize for their discovery of mechanisms
regulating cholesterol metabolism.

"I cannot
say enough about the NIH Clinical
Center. It's the place that restored
my faith in medicine. They cared
about my daughter, they cared
about me, they cared about how
we were treated, and offered
any help in any way. It's the
kindnesses that really stood
out—certainly that first
week that we were there. They
call it the place of last resort
because if the people there can't
help you, nobody can."

–Marybeth
Krummenacker, mother of a
cystinosis patient

“Somebody could go through the National
Academy of Sciences membership roster, especially
of the MDs, and count how many had actually
been at NIH,” says Brown. “I
imagine it’s a very significant percentage.
One could go through the list of people who
trained with Stadtman and Nirenberg, as an
example, and that would give you an incredible
who’s who in modern medical science.
Dr. Stadtman alone, the person I trained
with, has had two Nobel prize winners, me
and Stanley Prusiner, [and a long line of
exceptional physician-scientists]. We all
shared the same experience—coming out
of a clinical background and suddenly being
exposed to this incredibly clear and rigorous
thinker and to science at a level where you
could really reduce a problem down to simple
questions that could be answered by elegant
experiments. For all of us, it molded our
future lives. We just wanted to keep doing
it again and again.”

Some of the most important work in the Clinical
Center has involved the concept of inborn
errors of metabolism (biochemical reactions
in the body). Many metabolic diseases lead
to the buildup in cells of toxic products
that cause cell abnormalities known as “storage” diseases.
Features of these diseases vary depending
on the biochemical pathway affected—in
the patients Fredrickson and his colleagues
studied, these were lipid storage diseases.
Much of this work is conducted in laboratories,
where NIH scientists work with patients’ cell
lines and with tissue cultures. But the presence
of patients in the Clinical Center is a constant
reminder of the NIH mandate to improve the
nation’s health, not just its science.

One of the first NIH researchers to investigate
storage diseases was Roscoe Brady (NINDS),
who in 1956 began studying a rare inherited
disease called Gaucher’s disease. In
1964, Brady discovered, and the next year
described, the underlying enzyme defect in
Gaucher’s disease. Brady went on to
describe the enzyme deficiencies in Nemann-Pick
disease (1966) and Fabry’s disease
(1967) and with colleagues the specific defect
in Tay-Sachs disease (in 1969). In 1991,
he developed effective enzyme replacement
therapy for patients with Gaucher’s
disease, and more recently, has been instrumental
in getting approval for enzyme replacement
therapy for patients with Fabry disease.
Many researchers have followed his lead.
In 1983 he shared a Lasker Award with Elizabeth
Neufeld (NIDDK), who was recognized for identifying
the enzyme defect that causes mucopolysaccharide
(carbohydrate) storage disorders, and with
Robert Gallo, for his work leading to isolation
of the retrovirus HTLV-I.

Approaches to treatment being developed
for these storage disorders include enzyme
therapy, protein therapy, and gene therapy.
Bill Gahl (formerly with Child Health and
Human Development and now clinical director
of the National Human Genome Research Institute)
has saved many children from early death
through his work on a rare disorder called
cystinosis, a lysosomal storage disorder
that destroys the kidneys and other organs—for
which he has developed effective small-molecule
therapy.

Biological approaches
to cancer treatment

It was more difficult achieving cures with
solid tumors than with liquid tumors. Biological
approaches using the body’s immune
system are now being applied in cancer treatment.
Three kinds of treatment— surgery,
radiation therapy, and chemotherapy—will
cure half the people who develop cancer this
year. But the half who cannot be cured will
account for half a million deaths in America
alone, says Steven A. Rosenberg. In working
on a fourth therapeutic approach, Rosenberg’s
team in NCI is converting research on interleukin
and other cytokines into tools for adaptive
immunotherapy. Cutting across melanomas removed
from human patients and finding that some
of the cells that infiltrated the tumors
looked like immune cells, Rosenberg reasoned
they were there for a reason— and that
perhaps the body’s immune system could
be better harnessed to fighting the cancer
that surgery, radiation, and chemotherapy
fail to eliminate.

With tumor-infiltrating lymphocytes (or
TIL cells) taken from the tumor, Rosenberg’s
lab spent five years cloning the genes that
encode cancer antigens, learning how to generate
T cells that could recognize them. Then they
developed a mouse model of melanoma, showing
the effects of giving the mice IL-2. Having
done the preclinical science, they tested
the model on patients with faradvanced cases
of melanoma on whom all standard treatment
options had failed. Rosenberg took the TIL
cells out of the patients, expanded them,
revved them up, and gave them back to each
specific patient along with IL-2. Many patients
died, but the treatment also produced some
amazing turnarounds. A young boy with large
tumors on the chest and abdomen—expected
to die in six weeks—showed no signs
of cancer after four months of treatment.

When people talk about research at the Clinical
Center being “bench to bedside and
back again”—this is what they
are talking about. This pioneering use of
IL-2 and TIL cells to treat melanoma and
renal-cell cancer started at the laboratory
bench, translating human tumor cells into
a mouse model, expanded to treatment of patients
in the Clinical Center, and has returned
to the bench many, many times, for refining
of the model.

Patient perspectives

Needless to say, research in the Clinical
Center requires the teamwork and support
not only of scientists, physicians, and roughly
650 highly trained nurses, but also of specialists
in social work, nutrition, rehabilitation,
laboratory medicine, transfusion medicine,
imaging sciences, and pharmaceuticals, among
other fields. With so many immune-suppressed
patients in the building, and so many potentially
toxic chemicals, even the people who clean
patients’ rooms and who work on the
loading docks play critical roles in research
and health care.

Patient after patient interviewed for the
Clinical Center history expressed appreciation
that an intelligent, skilled, and knowledgeable
staff provides an intensity of care they
had not experienced before: no test was unimportant,
every result mattered, and yet patients were
not just the subjects of research. The staff
also showed compassion and a sense of dedication.
Patients and staff alike value the fact that
what’s going on in the Clinical Center
is important and will make a difference—and
not just in the lives of current patients.
Invariably they remark on staff teamwork
and on one of the most unusual features of
life in Building 10: that patients really
are considered partners in the research enterprise.

“Here at the Clinical Center we’re
all kind of learning things together,” says
Clenton Winford II, a patient with von Hippel-
Lindau syndrome who has been coming to the
Clinical Center since 1988, when the National
Cancer Institute began studying the hereditary
condition. “There is this sense of
community and solidarity. You’ve got
this confluence of all these people—both
patients and health workers—who are
trying to look for answers that we as a society
have never known. The physicians are always
willing to say, ‘This is what we know
and this is what we don’t know’ and
to admit that we’re all kind of on
this trek together. It’s much more
of a team environment, you might say, and
we are part of the team. Here we are not
only consumers but we are also producers.
Some of us have been told, ‘I’m
sorry. There’s nothing else we can
do. Get your affairs in order.’ At
least coming here, quite often, we’re
given hope. ‘We’ll try this one
more thing. We’re looking at this,
we’ll try to develop this, and if you’re
willing, we’ll do this together, and
we’ll all find out what happens.’”

Patients are also struck by the building-wide
sense of teamwork. “From day one, the
treatment I got at NIH was superior and still
remains that way,” says patient Ellen
Berty, who underwent an islet cell transplant
when her diabetes became life-threatening. “I
am part of that team, but it is an enormous
team. The team includes the parking lot attendants,
all the people I know in phlebotomy, all
of the nurses and the wonderful doctors on
my floor, all the specialists in dentistry
and dermatology. I know many people because
I’ve been involved in many procedures,
and they have always given me a special sense
that they really care about me personally
and what’s happening with me—not
just as part of their experiment, but me
personally. They’re so caring, every
single one. I think part of it is a lot of
people are at NIH as a last resort. You know,
they’ve tried their own doctors, they’re
willing to try something experimental because
what they’ve been living with has not
worked, and they don’t know what else
they can do. But I think part of the requirement
to work there is that you have to really
care about the people. The whole big team
is another concept that is critical to their
success, and it works for them.”

THE NIH CLINICAL CENTER
“There is no other hospital like it.”

1JAMA180:
1440, 1998.

This mini-history of the Clinical Center
is a sampler from a brief history of the
Clinical Center being researched and written
by Pat McNees. Yes, many stories and accomplishments
have been left out and Pat is at work learning
and writing about them. If you have a story
or accomplishment to share, please contact
the Clinical Center Office of Communications
at 301-496-2563 or send an e-mail note to
Pat McNees at pmcnees@compuserve.com,
providing details about how to get in touch
with you.

This is a participatory history, with an
emphasis on interviews and oral histories
and a de-emphasis on documents, especially
about official meetings. In connection with
this sampler, we thank Harvey Alter, Ellen
Berty, Vincent DeVita Jr., Tony Fauci, Emil
Frei, John Gallin, David Henderson, Harvey
Klein, Ann Plunkett, Cokie Roberts, Alan
Schechter, Thomas Waldmann, and Clenton Winford
II, although many others were interviewed
for it. The account of Clinical Center involvement
in the AIDS crisis was drawn both from interviews
with the people involved and from material
on the NIH History Office’s invaluable
website http://aidshistory.nih.gov where,
among other things, you can read oral history
interviews and hear the voices of researchers
recalling the early years of AIDS “in
their own words.”

Beacon of Hope: The NIH Clinical Center
Through 40 Years of Growth and Change, by
Richard Mandel, published for the Clinical
Center’s 40th anniversary, is available
online at http://history.nih.gov/history/,
along with other valuable resources.

An online videocast of a symposium on the
first ten years of intramural research in
NIMH and NINDS can be found at http://videocast.nih.gov/PastEvents.asp?c=4 for
April 11, 2003. Let us know of any similarly
rich sources of material about life and work
in the Clinical Center that we might have
missed.